NEUROBIOLOGY AND GENETICS OF PANIC, TS, AND OCD. This is an application for an NIMH K02 (Independent Scientist) award. The goal of the proposal is to continue specialized training for the PI, a psychiatrist, in molecular and population genetics. The aims of the research are to (a) locate genes affecting risk for panic disorder by genetic linkage; (b) identify genes influencing risk for Tourette's syndrome and obsessive-compulsive disorder using the haplotype relative risk (HRR) family association method; (c) identify genes associated with specific phenotypes (recognized, eg, by imaging studies) within groups affected with illness using association methods; and (d) identify specific mutations associated with phenotype by mutational analysis and sequencing. Under some circumstances, genome scan- directed linkage studies are most useful in identifying genes predisposing to illness; under other circumstances, HRR studies may be more efficient. For very strong candidate gene hypotheses, mutational analysis may be employed directly. Preliminary results have been generated using all of these methods. For our panic disorder linkage project ("a"), we have obtained DNA from 201 individuals in 21 families, as of May 1995. We have used the HRR method to identify a genetic association between Tourette's syndrome and an allele at the D4 dopamine receptor locus ('b"). In the area of genotype/phenotype association, we have reported an association between cocaine-induced paranoia and dopamine transporter alleles; we have obtained preliminary data using SPECT imaging techniques regarding the relationship between alleles at the D2 dopamine receptor locus (DRD2) and brain D2 receptor density ("c". We propose to complete a genome scan for the panic disorder linkage project; attempt to identify other genes influencing risk for Tourette's syndrome and obsessive-compulsive disorder; and identify other genotype-phenotype relationships using imaging studies as a way to ascertain phenotype directly.